Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment

Poli, Loris; Alberici, Antonella; Buzzi, P.J.; Marchina, Eleonora; Lanari, Alessia; Arosio, Cristina; Ciccone, Alfonso; Semeraro, Francesco; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara

doi:10.1007/s10072-016-2756-x

Cited by 29 publications

(18 citation statements)

References 10 publications

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“…Indeed, failure to reduce liver iron overload, as well as development of neurological symptoms, have been occasionally reported in ACP patients treated with phlebotomies (Hellman et al, 2000; Watanabe et al, 2018). In few cases, iron chelation has been combined with fresh frozen plasma (FFP) administration (aimed to restore CP levels), with transient beneficial effects in a couple of studies (Yonekawa et al, 1999; Poli et al, 2017). Other strategies are based on preventing oxidative tissue damage by administration of vitamin E or zinc sulfate (Pelucchi et al, 2018).…”

Section: Treatment Of Acp: Still Unsatisfactorymentioning

confidence: 99%

Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis

et al. 2019

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Aceruloplasminemia (ACP) is a rare, adult-onset, autosomal recessive disorder, characterized by systemic iron overload due to mutations in the Ceruloplasmin gene ( CP ), which in turn lead to absence or strong reduction of CP activity. CP is a ferroxidase that plays a key role in iron export from various cells, especially in the brain, where it maintains the appropriate iron homeostasis with neuroprotective effects. Brain iron accumulation makes ACP unique among systemic iron overload syndromes, e.g., various types of genetic hemochromatosis. The main clinical features of fully expressed ACP include diabetes, retinopathy, liver disease, and progressive neurological symptoms reflecting iron deposition in target organs. However, biochemical signs of the disease, namely a mild anemia mimicking iron deficiency anemia because of microcytosis and low transferrin saturation, but with “paradoxical” hyperferritinemia, usually precedes the onset of clinical symptoms of many years and sometimes decades. Prompt diagnosis and therapy are crucial to prevent neurological complications of the disease, as they are usually irreversible once established. In this mini-review we discuss some major issues about this rare disorder, pointing out the early clues to the right diagnosis, instrumental to reduce significant disability burden of affected patients.

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Section: Treatment Of Acp: Still Unsatisfactorymentioning

confidence: 99%

Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis

et al. 2019

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“…Overall, 13 different iron chelating methods have been administered, of which a detailed overview is included in Additional file 3. Monotherapy with deferoxamine or deferasirox has been most frequently reported, while combined iron chelation therapy was limited to 5 previously reported cases [8,17,40,44,48]. In these patients, phlebotomy was combined with deferasirox, deferiprone with deferoxamine, and fresh frozen plasma with deferoxamine or deferiprone.…”

Section: Review Of the Literaturementioning

confidence: 99%

Effects of iron chelation therapy on the clinical course of aceruloplasminemia: an analysis of aggregated case reports

Vroegindeweij

Wilson

Langendonk

2020

Orphanet J Rare Dis

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Background: Aceruloplasminemia is a rare genetic iron overload disorder, characterized by progressive neurological manifestations. The effects of iron chelation on neurological outcomes have only been described in case studies, and are inconsistent. Aggregated case reports were analyzed to help delineate the disease-modifying potential of treatment. Methods: Data on clinical manifestations, treatment and neurological outcomes of treatment were collected from three neurologically symptomatic Dutch patients, who received deferiprone with phlebotomy as a new therapeutic approach, and combined with other published cases. Neurological outcomes of treatment were compared between patients starting treatment when neurologically symptomatic and patients without neurological manifestations. Results: Therapeutic approaches for aceruloplasminemia have been described in 48 patients worldwide, including our three patients. Initiation of treatment in a presymptomatic stage of the disease delayed the estimated onset of neurological manifestations by 10 years (median age 61 years, SE 5.0 vs. median age 51 years, SE 0.6, p = 0.001). Although in 11/20 neurologically symptomatic patients neurological manifestations remained stable or improved during treatment, these patients were treated significantly shorter than patients who deteriorated neurologically (median 6 months vs. median 43 months, p = 0.016). Combined iron chelation therapy with deferiprone and phlebotomy for up to 34 months could be safely performed in our patients without symptomatic anemia (2/3), but did not prevent further neurological deterioration. Conclusions: Early initiation of iron chelation therapy seems to postpone the onset of neurological manifestations in aceruloplasminemia. Publication bias and significant differences in duration of treatment should be considered when interpreting reported treatment outcomes in neurologically symptomatic patients. Based on theoretical grounds and the observed long-term safety and tolerability in our study, we recommend iron chelation therapy with deferiprone in combination with phlebotomy for aceruloplasminemia patients without symptomatic anemia.

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“…In the small number of patients in which iron chelators were administered along with FFP early during the disease, iron deposition and neurological symptoms were reduced raising the possibility of a potential treatment strategy. 429 Neuroferritinopathy. Neuroferritinopathy is an autosomal dominant disorder caused by a number of different mutations in the L-ferritin gene that reduce the ability of ferritin to sequester iron resulting in increased free, unbound iron in the cytosol.…”

Section: Neurodegeneration With Brain Accumulation Disordersmentioning

confidence: 99%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

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All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

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Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment

Cited by 29 publications

References 10 publications

Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis

Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis

Effects of iron chelation therapy on the clinical course of aceruloplasminemia: an analysis of aggregated case reports

Overdosing on iron: Elevated iron and degenerative brain disorders

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